Alzheimer's disease is a neurodegenerative disorder, afflicting approximately 24 million people worldwide. The disease is characterised by cognitive and behavioural dysfunction resulting from loss of neurons and synapses in the cerebral cortex and certain sub-cortical regions of the brain.
The disease can begin many years before it is eventually diagnosed. In the early stages, short-term memory loss is the most common symptom. Later, symptoms include confusion, anger, mood swings, language breakdown, long-term memory loss, and the general decline of senses and bodily functions.
Alzheimer's disease is the most common type of dementia in the elderly and affects almost half of all patients with dementia. Correspondingly, advancing age is the primary risk factor for the disease. Among people aged 65, 2-3% show signs of the disease, while 25-50% of people aged 85 have symptoms of Alzheimer's and an even greater number have some of the pathological hallmarks of the disease without the characteristic symptoms. The World Health Organisation estimates that globally the total disability adjusted life years (DALY) for Alzheimer's disease and other dementias exceeded 11 million in 2005, with a projected 3.4% annual increase. There is at present no known cure for Alzheimer's disease, and available treatments offer relatively small symptomatic benefits and are palliative in nature.
Depression is a common early symptom in Alzheimer's disease and is believed to be attributed to, amongst other factors, up-regulation of the enzyme monoamine oxidase (MAO). There are two isoforms of this enzyme, MAO-A and MAO-B. Both are found throughout the cells of the central nervous system (CNS), where they function to inactivate monoaminergic neurotransmitters including phenethylamine and dopamine. MAO-B is also abundant in blood platelets.
The onset and progression of Alzheimer's disease is associated with the development of amyloid plaques and neurofibrillary tangles. Amyloid plaques (also known as “senile plaques”) comprise dense insoluble deposits of beta-amyloid, a protein derived from the transmembrane protein amyloid precursor protein (APP). Following the proteolysis of APP, beta-amyloid proteins aggregate extracellularly, forming plaques. Neurofibrillary tangles are formed due to hyperphosphorylation of tau, a microtubule-associated protein that is abundant in the CNS. Multiple hyperphosphorylated tau molecules become entangled and form masses within nerve cell bodies. Such neurofibrillary tangles cause microtubules to disintegrate, resulting in collapse of the neuronal transport system.
Alzheimer's disease is usually diagnosed clinically from the patient history, observations of relatives, and clinical observations. However, the presence of Alzheimer's disease-characteristic neurological and neuropsychological features such as amyloid plaques and neurofibrillary tangles can often only be determined post-mortem.
Most cases of Alzheimer's disease do not exhibit familial inheritance, however at least 80% of sporadic Alzheimer's cases involve genetic risk factors. Inheritance of the ε4 allele of the apolipoprotein E (ApoE) gene is regarded as a risk factor for development in up to 50% of late-onset sporadic Alzheimer's cases.
Glutathione S-transferase omega-1 (GSTO-1) is a member of the gluthathione S-transferase family of enzymes that catalyse the conjugation of reduced glutathione (GSH) with various hydrophobic substrates bearing electrophilic centres. The gene encoding GSTO-1 is known to exist in different genetic isoforms. These isoforms correlate with the age-at-onset (AAO) of Alzheimer's disease and Parkinson's disease (Li, Y et al., Hum Mol Genet. (2003) 12(24):3259-67). Li and co-workers described that the GSTO-1h SNP 7-1 (rs4825, A nucleotide) is associated with an AAO delay of 6.8 years (+/−4.41) for Alzheimer's disease and 8.6 years (+/−5.71) for Parkinson's disease (Li, Y et al., Neurobiol Aging (2006) 27(8):1087-93).
Diagnostic markers for neurological disorders are especially important in diagnosis early in the course of disease, when therapeutic compounds have the greatest potential effect. However, accurate diagnosis is difficult. Few diagnostic markers for early stage neuronal disorders are available and those that are available rely on the analysis of sample material (e.g. cerebrospinal fluid), which is difficult and painful to obtain.
Therefore, there is a need to identify new diagnostic methods using biomarkers of Alzheimer's disease which are available peripherally from easily obtainable patient samples, thereby aiding simple and accurate diagnosis.